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Hyper-IgM Syndrome

by James Fernandez, MD, PhD

Hyper-IgM syndrome is an Ig deficiency characterized by normal or elevated serum IgM levels and decreased levels or absence of other serum Igs, resulting in susceptibility to bacterial infections.

Hyper-IgM syndrome may be X-linked or autosomal. Manifestations vary depending on the mutation and its location.

Most cases are X-linked and caused by mutations in a gene on the X chromosome that encodes a protein (CD154, or CD40 ligand) on the surfaces of activated helper T cells. In the presence of cytokines, normal CD40 ligand interacts with B cells and thus signals them to switch from producing IgM to producing IgA, IgG, or IgE. In X-linked hyper-IgM syndrome, T cells lack functional CD40 ligand and cannot signal B cells to switch. Thus, B cells produce only IgM; IgM levels may be normal or elevated. Patients with this form may have severe neutropenia and often present during infancy with Pneumocystis jirovecii pneumonia. Lymphoid tissue is very small because deficient CD 40 ligand signaling does not activate B cells. Otherwise, clinical presentation is similar to that of X-linked agammaglobulinemia (see X-linked Agammaglobulinemia) and includes recurrent pyogenic bacterial sinopulmonary infections during the first 2 yr of life. Susceptibility to Cryptosporidium infections may be increased. Many patients die before puberty, and those who live longer often develop cirrhosis or B-cell lymphomas.

In autosomal recessive hyper-IgM syndrome with CD40 mutation, manifestations are similar to those of the X-linked form.

At least 4 autosomal recessive forms involve a B-cell defect. In 2 of these forms (deficiency of activation-induced cytidine deaminase [AID] or uracil DNA glycosylase [UNG]), serum IgM levels are much higher than in the X-linked form; lymphoid hyperplasia (including lymphadenopathy, splenomegaly, and tonsillar hypertrophy) is present, and autoimmune disorders may be present. Leukopenia is absent.


  • CD40 ligand expression and genetic testing

Diagnosis is suspected based on clinical criteria. Serum Ig levels are measured; normal or elevated serum IgM levels and low levels or absence of other Igs support the diagnosis. Flow cytometry testing of CD40 ligand expression on T-cell surfaces should be done. When possible, the diagnosis is confirmed by genetic testing. Prenatal genetic testing can be offered to women considering pregnancy if they have a family history of CD40 ligand deficiency. Genetic testing of other relatives is not routinely done.

Other laboratory findings include a reduced number of memory B cells (CD27) and absence of class-switched memory B cells (IgD-CD27).


  • Prophylactic IV immune globulin (IVIG) and sometimes trimethoprim/sulfamethoxazole

  • Bone marrow transplantation when possible

Treatment usually includes IVIG 400 mg/kg once/mo. Patients with the X-linked form or CD40 mutations are given trimethoprim/sulfamethoxazole to prevent P. jirovecii infection, and environmental precautions are taken to reduce the risk of Cryptosporidium infection (see Overview of Gastroenteritis : Prevention). However, because the prognosis is poor, bone marrow transplantation is preferred if an HLA-identical sibling donor is available.

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